Physical therapy is widely used during traumatic brain injury (TBI) rehabilitation. However most of the knowledge concerning the effects of exercise on recovery from TBI has been based on observation, and scientifically based research regarding the effects of exercise on recovery from TBI is scant. Previous studies have indicated that voluntary exercise promotes recovery from concussive brain injury. In particular, post-TBI voluntary exercise increases levels of brain derived neurotrophic factor (BDNF) and other key molecules involved in neuroplasticity. However, when exercise is provided acutely after injury there is no increase in BDNF and behavioral outcome worsens. This proposal will continue this line of research by testing the hypothesis that early post-traumatic stress response-induced elevation in glucocorticoids blunts the effects of exercise-induced BDNF upregulation. The effects of stress on BDNF will be investigated in rats through utilizing different exercise regimens during the first week (acute) and later-weeks after TBI. Because sustained stress is likely to decrease BDNF and downstream molecules, some forms of exercise may encumber recovery of function after TBI. The first experiments within this proposal will determine if injury induced alterations in levels of corticosterone (CORT) play a key role in the disruption of BDNF mediated neuroplasticity during different post-TBI time periods. CORT is the main circulating glucocorticoid in rats. These experiments will provide the framework to determine if some exercise regimens can prolong or foment injury-induced disruptions in glucocorticoids. The effects of non-self-regulated (forced) and self-regulated (voluntary) exercise will be compared during the acute and later-weeks after TBI. These forms of exercise are likely to produce different stress responses that will consequentially influence BDNF upregulation and ultimately have an effect on recovery or outcome. Forced exercise is more intensive in that it is administered in relatively short sessions, making it more akin to current physical therapy. In contrast voluntary exercise is spaced throughout the active period of the day. Finally this proposal will determine if stress alleviation through the use of antidepressant treatment can reverse stress-induced changes in BDNF. A substantial number of TBI patients are diagnosed and treated for disorders that are associated with glucocorticoid disregulation, such as depression and post- traumatic stress disorder (PTSD). Antidepressants, which are widely administered in the rehabilitative period, are associated with upregulating BDNF and decreasing levels of glucocorticoids. The effects of a selective norepinephrine and serootonergic uptake inhibitors will be studied. It is expected that antidepressant treatment will decrease levels of CORT and enhance exercise-dependent BDNF increases. Ultimately these studies will aid in developing adequate exercise regimens that endogenously increase levels of BDNF and associated molecules at a time that is pertinent to the rehabilitative time-period. PUBLIC HEALTH RELEVANCE: Those affected with brain injury endure long-lasting impairments that have a strong impact on life quality. We will investigate the effects of different post-injury exercise regimens on recovery and how these can be influenced by stress. This proposal will provide mechanistically based information that will aid in developing an optimal exercise regimen after TBI.